1. Field of the Invention
The present invention relates to the preparation and use of amino-acyl-type and catecholamine-type hepatobiliary and cardiac contrast agents useful in magnetic resonance imaging. The contrast agents have multiple carboxyl groups to chelate a variety of metal (II) or (III) ions.
2. Description of Related Art
This invention relates to contrast agents for medical magnetic resonance imaging (MRI).
A contrast agent is an exogenous substance that either augments or suppresses the normal in vivo MRI signal, thereby yielding additional diagnostic information. The theory and applications of various types of contrast agents have been described in the literature (1,2). The Arabic numbers in parentheses in this section refer to the articles cited in this section.!
The applications of a given MRI contrast agent are determined by its distribution in vivo. The mechanisms controlling the initial biodistribution can be classed as physico-chemical, i.e., dependent only upon such properties as molecular size, charge, lipophilicity, surface properties, etc.; or receptor-mediated, i.e., dependent upon the binding of a substrate to a specific receptor in or on cells. Different organs may handle the same contrast agent by different mechanisms. For example, the molecular size of the agent may result in its filtration by the kidneys (or confinement to the vascular space) while it is cleared by receptor-mediated transport in the liver.
Contrast agents exhibiting a physico-chemical distribution mechanism include the gadolinium (III) complex of diethylenetriaminepentaacetic acid (Gd-DTPA), which distributes in blood plasma and extracellular fluid, and albumin-(Gd-DTPA).sub.n, which remains largely intravascular (1,2). The former is used to demonstrate blood-brain barrier lesions or to reveal renal anatomy and function (3), while the latter has been used experimentally to delineate the vasculature (4) and determine brain blood volume (5,6). Iron-dextran, although a colloid, has a sufficiently long plasma half-life (12 hr) to be used as an intravascular T2 contrast agent (7), as do some superparamagnetic iron oxide particle preparations (8,9).
Because of its role in the removal of exogenous compounds from general circulation, the liver is able to actively take up and concentrate soluble, as well as particulate, contrast agents. The pathways followed by solutes from plasma to bile have been reviewed (10-11) and are diagrammed in FIG. 4. Passage into the hepatocyte across the cell membrane can take place by pinocytosis, passive diffusion, and/or by carrier-mediated systems that transport bile acids, bilirubin, organic anions, organic cations, neutral organic compounds, or inorganic ions. The substrate specificity of different carrier systems can partially overlap (e.g., organic anions and bile acids). The substrate may be metabolized intracellularly and/or conjugated with glucuronic acid or glutathione, for example. Finally, excretion into bile canaliculi again involves passage through a cell membrane. The mechanism of biliary excretion for a given compound may differ from that operative for its uptake.
The relative rates of metabolism, biliary elimination, and renal excretion determine the clearance of drugs and their metabolites from blood plasma and their persistence in any one organ system. However, presently the factors that direct one compound to be excreted in the bile and another in the urine are not completely understood. Molecular weight, polarity, and molecular structure in relation to binding to plasma and transporter proteins are important. There appears to be a general molecular weight threshold, which is species-dependent (ca. 300 for rats and 600 for humans) below which urinary excretion dominates (10-11). Hydrophilic-lipophilic balance appears to play a critical role in biliary excretion (10-11). However, a priori prediction is not presently possible.
The liver has provided the first example of receptor-mediated localization of an MR contrast agent--Fe-EHPG (EHPG is Ethylene-bis(hydroxyphenylglycine)) (12). Other iron (13-15), manganese (16-17), and gadolinium (18) chelates have since been described that have either potential for, or have demonstrated receptor-mediated hepatocyte uptake.
It has been reported by others that the anionic chelates Fe-EHPG, Fe-HBED (HBED=bis-(hydroxybenzyl) ethylenediaminediacetic acid), and Fe-PGDF (PGDF=N-3-(phenylglutaryl) desferrioxamine B) are transported in the liver by a system or systems inhibitable by BSP (bromosulfophthalein) (13,15).
The lipophilic chelate Gd-BOPTA ("benzyloxypropionic-tetraacetate," a derivative of DTPA) was shown to have significant biliary excretion (38.6% of injected dose in bile at 6 hr) (18). No information was reported on the mechanism of transport (e.g., passive diffusion or anionic transport) of this compound. Gd-BOPTA produced a larger signal enhancement (48%) in liver than Gd-DTPA (16%) in T1-weighted spin-echo images at 0.5 Tesla.
Additionally, other organs and tissues may possess receptors with affinity for certain classes of substrates, e.g., amino acids, peptides or catechol amines (19-24). These receptors may also bind molecules that resemble the substrate, e.g., a derivative of an amino acid that is present in a peptide substrate (22) or an amide derivative of a naturally occurring catechol amine such as dopamine. The contrast agents of this invention may in part localize by such a mechanism. Furthermore, the localization of the catechol containing contrast agent of the present invention may depend in part on their respective reduction-oxidation properties.
To date, magnetic resonance imaging (MRI) has played a minor role in imaging of the liver and abdomen of a human being because of degradation of image quality by motion artifacts, and by the lack of suitable contrast agents. Recent technical advances in instrumentation (e.g., self-shielded gradient coils) and pulse sequences (e.g., echo-planar and turbo-flash techniques) promise to alleviate the motion-related problems of the torso and abdomen, and make contrast agent development all the more important for continued progress in abdominal MRI.
General background in the use of MRI contrast agents and of their preparation and purification are described, for example, in:
H. Gries et al., U.S. Pat. No. 4,647,447; PA1 R. B. Lauffer et al., U.S. Pat. No. 4,899,755 and 4,880,008; PA1 B. L. Engelstad et al., U.S. Pat. No. 4,909,257; PA1 D. L. White et al., U.S. Pat. No. 4,999,445. PA1 1. R. B. Lauffer, "Paramagnetic metal complexes as water proton relaxation agents for NMR imaging: Theory and Design," Chem. Rev. (1987); 87:901-927. PA1 2. S. M. Rocklage, et al. "Contrast Agents in Magnetic Resonance Imaging." Chapter 14, in Magnetic Resonance Imaging, 2nd ed., Stark D. D., Bradley W. G., eds. St. Louis: C. V. Mosby Co. (1992). PA1 3. G. Bydder, "Clinical applications of Gadolinium-DTPA." in Magnetic Resonance Imaging. Stark D. D., Bradley W. G., eds. St. Louis: C. V. Mosby Co. (1988); 182-200 (Chap. 10). PA1 4. M. E. Moseley et al., "Vascular mapping using Albumin-(Gd-DTPA), an intravascular MR contrast agent, and projection MR imaging," J. Computer Assist Tomography (1988); 13:219-221. PA1 5. T. A. Kent et al., "Cerebral blood volume in a rat model of cerebral ischemia by MR imaging at 4.7 T,"AJNR (1989); 10:335-358. PA1 6. D. L. White et al., "Determination of perfused cerebral blood volume using an intravascular MR contrast agent," Book of Abstracts: Society of Magnetic Resonance in Medicine (1989); 2:806. PA1 7D. L. White et al., "Iron-Dextran as a magnetic susceptibility contrast agent: Flow-related contrast effects in the T2-weighted spin-echo MRI of normal rat and cat brain," Magn.Reson.Med. (1992); 24:14-28. PA1 8. D. L. White et al., "Plasma clearance of ferrosomes, a long-lived superparamagnetic MRI contrast agent." Book of Abstracts: Society of Magnetic Resonance in Medicine (1990); 1:51. PA1 9. R. Weissleder et al., "Ultrasmall superparamagnetic iron oxide: Characterization of a new class of contrast agent for MR imaging," Radiology (1990); 175:489-493. PA1 10. L. S. Schanker, "Secretion of organic compounds into bile." in The Handbook of Physiology. Alimentary Canal V. Washington, D.C.: American Physiol. Society, Chap. 114:2433-2449. PA1 11. C. D. Klaassen et al., "Mechanisms of bile formation, hepatic uptake, and biliary excretion," Pharm. Rev. (1984); 36:1-67. PA1 12. R. B. Lauffer et al., "Iron-EHPG as a hepatobiliary MR contrast agent: Initial imaging and biodistribution studies," J. Computer Assist. Tomoaraph, (1985); 9:431-438. PA1 13. B. Hoener et al., "Evaluation of Fe-HBED and Fe-EHPG as magnetic resonance contrast agents for assessing hepatobiliary function," J. Magn. Reson. Imaging, (1991); 1:357-362. PA1 14. K. A. Muetterties et al., "Ferrioxamine B derivatives as hepatobiliary contrast agents for magnetic resonance imaging," Magn. Reson. Med. (1991); Vol. 22, pp. 88 to 100. PA1 15. B. Hoener et al., "Hepatic transport of the magnetic resonance imaging contrast agent Fe(III)-N-(3-Phenyl-glutaryl) desferrioxamine B," Magn. Reson. Med. (1990); 17:509-51. PA1 16. D. L. White et al., "Clearance, excretion, and organ distribution of a new MRI contrast agent Manganese-Dipyridoxal-Diphosphate (Mn-DPDP)." Abstract Book: Society of Magnetic Resonance in Medicine (1988) 1:531. PA1 17. S. W. Young, "MRI measurement of hepatocyte toxicity using the new MRI contrast agent manganese dipyridoxal diphosphate, a manganese/pyridoxal 5-phosphate chelate," Mag. Reson. Med. (1989); 10:1-13. PA1 18. P. Pavone et al., "Comparison of Gd-BOPTA with Gd-DTPA in MRI imaging of rat liver," Radiology (1990); 176:61-64. PA1 19. P. Ascher, "Glutamate receptors and glutamatergic synapses. In Receptors. Membrane Transport and Signal Transduction. A. E. Evangelopoulis et al., Berlin: Springer Verlag. (1989): 127-146. PA1 20. F. P. Lehman, "Stereoselective Molecular Recognition in Biology. In Receptors and Recopnition, Vol. 5, Series A. Cuatrecasas P. and Greaves M. F. London: Chapman-Hall (1978). PA1 21. R. D. O'Brien, ed. The Receptors, A Comprehensive Treatise, Vol. 1, New York: Plenum Press (1979). PA1 22. S. S. Schiffman et al., "The Search for Receptor that Mediate Sweetness," In The Receptors, Vol. 4, Conn, P. M., ed. Academic Press. Orlando. (1986). PA1 23. A. S. Horn, et al., eds. The Neurobiology of Dopamine. Academic Press. New York. 1979. PA1 24. B. J. Clark. "The role of dopamine in the periphery," in The Dopaminergic System, B. Halasz, et al., eds., Springer-Verlag, Berlin, 1985, p 27-39. PA1 wherein M is a metal (II) or (III) ion independently selected from the group consisting of metals of atomic number 21 to 31, metals of atomic number 39 to 50, the lanthanide metals having an atomic number from 57 to 71, and metals of atomic number 72 to 82; and PA1 L.sup.1 is a polydentate amino-acyl-type chelating moiety of Formula 1: ##STR1## wherein Q, J, X, X' and Z are each independently selected from the group consisting of --CH.sub.2 --(C.dbd.O)OR.sup.1 and --CH.sub.2 --(C.dbd.O)--NH--CH(R)(A); PA1 wherein each R is independently selected from the group consisting of -hydrogen, --K, --W and --K--W, wherein each K is an alkyl group having 1-7 carbon atoms, and each W is independently selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; and PA1 m is selected from 0, 1, 2 or 3, and PA1 n is selected from 0 or 1; PA1 or the pharmaceutically acceptable salt(s) thereof. PA1 (a) contacting a structure of the following formula: ##STR2## wherein D and E are CH.sub.2 (C.dbd.O)OR.sup.1, with an amino acid of the structure H.sub.2 N--CH(R)--(C.dbd.O)OH, an ester of the structure H.sub.2 N--CH(R)--(C.dbd.O)OR.sup.1 or an amide of the structure H.sub.2 N--CH(R)--(C.dbd.O)--N(R.sup.2)(R.sup.3); PA1 wherein each R is independently selected from the group consisting of --K, --W and --K--W, wherein each K is an alkyl group having 1-7 carbon atoms, and each W is independently selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; PA1 R.sup.1, R.sup.2 and R.sup.3 are independently selected from the group consisting of hydrogen (i.e. the acid), alkyl having 1-7 carbon atoms, cyclohexyl, phenyl, benzyl, 1-naphthyl and 2-naphthyl, and PA1 m is selected from 0, 1, 2 or 3, and PA1 n is selected from 0 or 1, PA1 in an anhydrous dipolar aprotic solvent at between about 50 and 150.degree.; and PA1 (b) removing the solvent and recovering the compound of Formula 1. PA1 (a) injecting the mammal with an amino-acyl-type contrast agent in a dose amount having a concentration of the complex L.sup.1 --M of between about 0.5 and 5000 micromol/kg of body weight of the mammal; PA1 (b) placing the mammal of step (a) in a magnetic field irradiating with radio-frequency energy such that nuclear magnetic resonance can be detected; and PA1 (c) analyzing the imaging nuclear magnetic resonance signals obtained. PA1 L.sup.2 is a polydentate catecholamine-type chelating moiety of Formula 2: ##STR3## wherein G, T, V, V' and Y are each independently selected from the group consisting of --CH.sub.2 --(C.dbd.O)OR.sup.1 and --CH.sub.2 --(C.dbd.O) --NH--CH.sub.2 --R.sup.4 ; PA1 wherein each R.sup.4 is independently selected from the group consisting of --CH.sub.2 -aryl, --CH.sub.2 CH.sub.2 -aryl, --CH.sub.2 -(substituted aryl), and --CH.sub.2 CH.sub.2 -(substituted aryl); and PA1 m is selected from 0, 1, 2 or 3, and PA1 n is selected from 0 or 1; PA1 or the pharmaceutically acceptable salt(s) thereof. PA1 (a) contacting a structure of the following formula: ##STR4## wherein D and E are CH.sub.2 (C.dbd.O)OR.sup.1, with a derivative of the structure NH.sub.2 --CH.sub.2 --R.sup.4 ; wherein R.sup.4 is independently selected from the group consisting of --CH.sub.2 -aryl, --CH.sub.2 CH.sub.2 -aryl, --CH.sub.2 -(substituted aryl), and --CH.sub.2 CH.sub.2 -(substituted aryl); and PA1 m is selected from 0, 1, 2 or 3, and PA1 n is selected from 0 or 1, PA1 in an anhydrous dipolar aprotic solvent at between about 50 and 150.degree.; and PA1 (b) removing the solvent and recovering the compound of Formula 2. PA1 (a) injecting the mammal with a catecholamine-type contrast agent in a dose amount having a concentration of the complex L.sup.2 --M of between about 0.5 and 5000 micromol/kg of body weight of the mammal; PA1 (b) placing the mammal of step (a) in a magnetic field irradiating with radio-frequency energy such that nuclear magnetic resonance can be detected; and PA1 (c) analyzing the imaging nuclear magnetic resonance signals obtained.
All reference articles, patents, etc. cited in this application are incorporated herein by reference in their entirety.
It would be very useful to have organic chelate metal ion complexes which are specific for MRI imaging of the liver, the biliary tree, the upper small intestine, or the myocardial tissue. The present invention provides complexes and methods having these useful advantages.